In 1988, 'Til Tuesday released Everything's Different Now, their third and final album. Shortly after its release, Mann said that she was much more pleased with it than the band's debut album, primarily because she felt it made more of a personal statement about her life.[8] The album contained the song "The Other End (Of the Telescope)" which Mann wrote and sang with Elvis Costello, but it was the track "(Believed You Were) Lucky" which was selected as the album's only single, with "Limits to Love" on the B-side.[9]

'Til Tuesday broke up in 1990 when Mann left to start her solo career.[7]

In 2002, Mann released Lost in Space, an album which features art by Seth. The song High on Sunday 51 from this album was used on the soundtrack of Third Watch, Season 4, Episode 13 (Snow Blind). The following year she released Lost in Space Special Edition, which features a second disc containing six live recordings (including a version of Coldplay's "The Scientist") as well as two B-sides and two previously unreleased songs.

In 2005, Mann released The Forgotten Arm, a concept album set in the 1970s about two lovers who meet at the Virginia State Fair and go on the run. The Joe Henry-produced album, which was recorded mostly live with few overdubs, contains illustrations which reflected Mann's interest in boxing. She trained with the boxing trainer Freddie Roach;[12] the album's title is derived from a boxing move in which one arm is used to hit the opponent, causing him to "forget" about the other, which is then used to deliver a harsher blow. The following year, Mann received a Grammy Award for Best Recording Package for her contribution in the album's artwork (shared with Gail Marowitz).[13]

In 2006, Mann released One More Drifter in the Snow, a Christmas album featuring both covers and new songs. The album's iTunes version replaced "Christmastime" (a duet with husband Michael Penn) with a cover of Joni Mitchell's "River" and "Clean Up for Christmas" from The Forgotten Arm; an updated version of the CD was released two years later with the Joni Mitchell cover.

In 2008, Mann released @#%&*! Smilers, which features Grammy-nominated artwork by Gary Taxali. The album debuted on the Billboard 200 at number 32 and on the Top Independent Albums chart at number 2.[14]@#%&*! Smilers was met with mostly praise, with Billboard stating that it "pops with color, something that gives it an immediacy that's rare for an artist known for songs that subtly worm their way into the subconscious... Smilers grabs a listener, never making him or her work at learning the record, as there are both big pop hooks and a rich sonic sheen."[15] The music video for the song "31 Today", directed by Bobcat Goldthwait, features comedian Morgan Murphy.[16]

In 2009, Mann announced that she was working on a musical based on her album The Forgotten Arm[17] but later stated that it was put on hold owing to similarities to the film The Fighter (2010).

In 2010, Mann joined the 9th Annual Independent Music Awards judging panel to promote independent musicians.[18][19][20] She was also an inaugural member of the panel in 2001.[21]

In 2012, Mann released Charmer, an album which features a duet with James Mercer of the Shins. Two singles were released from the album - the title track, which featured a music video directed by The Best Show's Tom Scharpling; and "Labrador," which featured actor Jon Hamm and references to Mann's music video work with 'Til Tuesday.

In February 2013, Mann and Ted Leo started playing together in a collaborative project called #BOTH and scheduled shows in Los Angeles and San Francisco.[22] The band name was later changed to the Both. In April 2014, she collaborated with Leo on The Both, their first album.[23] Mann co-wrote the album, as well as providing bass and co-lead vocals alongside Leo.

On July 22, 2013, Mann filed a lawsuit against MediaNet Digital Inc. claiming they were distributing 120 of her songs on an expired license agreement.[24] She attempted to claim as much as $18 million in statutory damages.[25] The case has since been dropped.[26]

In February 2014, Mann appeared in an episode of the popular cartoon Steven Universe as the fusion gem Opal.

In October 2016, Mann released a new song, "Can't You Tell," which was part of the 30 Days 30 Songs campaign in which musicians put out previously unreleased music in protest of then presidential candidate Donald Trump.

In January 2017, Mann announced Mental Illness, her ninth solo album. The album's lead single, "Goose Snow Cone," was released on the same day. On March 27 Mann performed the song with Jon Batiste and Stay Human on Late Show with Stephen Colbert. The album was released on March 31, 2017; with Mann releasing the album independently with distribution, marketing, and promotion through Membran Entertainment Group. The album won the Grammy Award for Best Folk Album at the 60th Annual Grammy Awards, Mann's second win.[27]

In September 2017, Mann contributed a song "Everybody Bleeds" to Season 1, episode 2 of the Netflix original series Big Mouth.

In 1997, Mann married songwriter Michael Penn (brother of actors Sean Penn and Chris Penn), whom she met in the 1980s. They courted while Mann was recording Whatever. Mann had previously been in a relationship with XTC guitarist David Gregory.

In 2007, she contributed vocals on the song "Unforgiven" from John Doe's album A Year In The Wilderness.

In 2012, she contributed vocals to Steve Vai's album The Story of Light, on the song "No More Amsterdam". That same year, she recorded the song "Two Horses" for the soundtrack of the film Tim and Eric's Billion Dollar Movie. Her song "Wise Up" was also used for an organ-donor campaign in Ontario.[29] She contributed vocals to the song "Bigger Than Love" on Ben Gibbard's album Former Lives.[30]

In 2002, Mann and her band appeared as themselves in Buffy the Vampire Slayer, performing her songs "This Is How It Goes" and "Pavlov's Bell" at the Bronze. She has one line in the episode: "Man, I hate playing vampire towns." The latter song also appears on the Buffy soundtrack album Radio Sunnydale. Also that year, she and her band appeared on The West Wing, where they performed a cover of James Taylor's "Shed a Little Light" at a Rock the Vote concert.[33]

On November 20, 2014, Mann appeared with Dana Gould and Nick Offerman on @midnight on Comedy Central,[36] and on March 21, 2016, Mann made a second appearance on the show with Jonathan Coulton and Dave Hill.

On August 19, 2015 Mann appeared with the Both band member Ted Leo on Conan performing an unsolicited campaign song for 2016 presidential candidate Lincoln Chafee.

On January 24, 2018, Mann appeared as the character Peg Peterson on Comedy Central's Corporate in the episode "The Pain of Being Alive". She plays the part of an employee of the Hampton DeVille Company with a very desirable parking space. Mann does not sing and no songs are credited to her in this episode, although her song "Nothing is Good Enough" plays as her character is hit by a car.